rs3752462

Variant names:

• chr22-36314138-T-C
• rs3752462
• NM_002473.6:c.1554+7A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-36314138-T-C
• chr22-36314138-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002473.6(MYH9):​c.1554+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,613,278 control chromosomes in the GnomAD database, including 324,968 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23800 hom., cov: 32)
  • Exomes 𝑓: 0.63 (301168 hom.)
• Consequence: MYH9 NM_002473.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002338
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.149
• Publications: 73 publications found

Genes affected

MYH9 (HGNC:7579): (myosin heavy chain 9) This gene encodes a conventional non-muscle myosin; this protein should not be confused with the unconventional myosin-9a or 9b (MYO9A or MYO9B). The encoded protein is a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain which is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in this gene have been associated with non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness. [provided by RefSeq, Dec 2011]

MYH9 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 17

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• May-Hegglin anomaly

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 22-36314138-T-C is Benign according to our data. Variant chr22-36314138-T-C is described in ClinVar as Benign. ClinVar VariationId is 44550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002473.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	NM_002473.6	MANE Select	c.1554+7A>G		splice_region intron	N/A	NP_002464.1	P35579-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.1554+7A>G		splice_region intron	N/A	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.1554+7A>G		splice_region intron	N/A	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.1554+7A>G		splice_region intron	N/A	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80197 AN: 152024 Hom.: 23805 Cov.: 32

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.761

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.676

Gnomad OTH AF: 0.549

GnomAD2 exomes AF: 0.565 AC: 142047 AN: 251232 AF XY: 0.565

Gnomad AFR exome AF: 0.256

Gnomad AMR exome AF: 0.630

Gnomad ASJ exome AF: 0.532

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.653

Gnomad NFE exome AF: 0.674

Gnomad OTH exome AF: 0.607

GnomAD4 exome AF: 0.631 AC: 921801 AN: 1461136 Hom.: 301168 Cov.: 58 AF XY: 0.625 AC XY: 454592 AN XY: 726894

African (AFR) AF: 0.252 AC: 8428 AN: 33464

American (AMR) AF: 0.631 AC: 28210 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 13783 AN: 26134

East Asian (EAS) AF: 0.219 AC: 8684 AN: 39696

South Asian (SAS) AF: 0.412 AC: 35570 AN: 86242

European-Finnish (FIN) AF: 0.655 AC: 34997 AN: 53406

Middle Eastern (MID) AF: 0.509 AC: 2933 AN: 5762

European-Non Finnish (NFE) AF: 0.678 AC: 753840 AN: 1111346

Other (OTH) AF: 0.586 AC: 35356 AN: 60374

GnomAD4 genome AF: 0.527 AC: 80198 AN: 152142 Hom.: 23800 Cov.: 32 AF XY: 0.523 AC XY: 38874 AN XY: 74376

African (AFR) AF: 0.269 AC: 11176 AN: 41516

American (AMR) AF: 0.611 AC: 9346 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 1830 AN: 3466

East Asian (EAS) AF: 0.222 AC: 1151 AN: 5178

South Asian (SAS) AF: 0.385 AC: 1856 AN: 4818

European-Finnish (FIN) AF: 0.652 AC: 6891 AN: 10568

Middle Eastern (MID) AF: 0.521 AC: 152 AN: 292

European-Non Finnish (NFE) AF: 0.676 AC: 45952 AN: 67992

Other (OTH) AF: 0.544 AC: 1150 AN: 2114

Alfa AF: 0.614 Hom.: 89738

Bravo AF: 0.515

Asia WGS AF: 0.255 AC: 889 AN: 3478

EpiCase AF: 0.665

EpiControl AF: 0.663

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Autosomal dominant nonsyndromic hearing loss 17 (2)
-	-	1	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (1)
-	-	1	MYH9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.5
DANN	Benign	0.56
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3752462; hg19: chr22-36710183;